Latest Articles Include:
- Editorial board and publication information
- J Biomech 43(1):IFC (2010)
- Innovations in Cell Mechanobiology
David Merryman W Engler AJ - J Biomech 43(1):1 (2010)
- In the middle of it all: Mutual mechanical regulation between the nucleus and the cytoskeleton
Dahl KN Booth-Gauthier EA Ladoux B - J Biomech 43(1):2-8 (2010)
The nucleus is typically treated as the large phase-dense or easy-to-label structure at the center of the cell which is manipulated by the governing mechanical machinery inside the cytoplasm. However, recent evidence has suggested that the mechanical properties of the nucleus are important to cell fate. We will discuss many aspects of the structural and functional interconnections between nuclear mechanics and cellular mechanics in this review. There are numerous implications for the progression of many disease states associated with both nuclear structural proteins and cancers. The nucleus itself is a large organelle taking up significant volume within the cell, and most studies agree that nuclei are significantly stiffer than the surrounding cytoplasm. Thus when a cell is exposed to force, the nucleus is exposed to and helps resist that force. The nucleus and nucleoskeleton are interconnected with the cellular cytoskeleton, and these connections may aid in helping di! sperse forces within tissues and/or with mechanotransduction. During translocation and transmigration the nucleus can act as a resistive element. Understanding the role of mechanical regulation of the nucleus may aid in understanding cellular motility and crawling through confined geometries. Thus the nucleus plays a role in developing mechanical territories and niches, affecting rates of wound healing and allowing cells to transmigrate through tissues for developmental, repair or pathological means. - Mechanics of the F-actin cytoskeleton
Stricker J Falzone T Gardel ML - J Biomech 43(1):9-14 (2010)
Dynamic regulation of the filamentous actin (F-actin) cytoskeleton is critical to numerous physical cellular processes, including cell adhesion, migration and division. Each of these processes require precise regulation of cell shape and mechanical force generation which, to a large degree, is regulated by the dynamic mechanical behaviors of a diverse assortment of F-actin networks and bundles. In this review, we review the current understanding of the mechanics of F-actin networks and identify areas of further research needed to establish physical models. We first review our understanding of the mechanical behaviors of F-actin networks reconstituted in vitro, with a focus on the nonlinear mechanical response and behavior of "active" F-actin networks. We then explore the types of mechanical response measured of cytoskeletal F-actin networks and bundles formed in living cells and identify how these measurements correspond to those performed on reconstituted F-actin ! networks formed in vitro. Together, these approaches identify the challenges and opportunities in the study of living cytoskeletal matter. - A multi-scale approach to understand the mechanobiology of intermediate filaments
Qin Z Buehler MJ Kreplak L - J Biomech 43(1):15-22 (2010)
The animal cell cytoskeleton consists of three interconnected filament systems: actin microfilaments, microtubules and the lesser known intermediate filaments (IFs). All mature IF proteins share a common tripartite domain structure and the ability to assemble into 8–12 nm wide filaments. At the time of their discovery in the 1980s, IFs were only considered as passive elements of the cytoskeleton mainly involved in maintaining the mechanical integrity of tissues. Since then, our knowledge of IFs structure, assembly plan and functions has improved dramatically. Especially, single IFs show a unique combination of extensibility, flexibility and toughness that is a direct consequence of their unique assembly plan. In this review we will first discuss the mechanical design of IFs by combining the experimental data with recent multi-scale modeling results. Then we will discuss how mechanical forces may interact with IFs in vivo both directly and through the activation of ot! her proteins such as kinases. - Mechanics of microtubules
Hawkins T Mirigian M Selcuk Yasar M Ross JL - J Biomech 43(1):23-30 (2010)
Microtubules are rigid cytoskeletal filaments, and their mechanics affect cell morphology and cellular processes. For instance, microtubules for the support structures for extended morphologies, such as axons and cilia. Further, microtubules act as tension rods to pull apart chromosomes during cellular division. Unlike other cytoskeletal filaments (e.g., actin) that work as large networks, microtubules work individually or in small groups, so their individual mechanical properties are quite important to their cellular function. In this review, we explore the past work on the mechanics of individual microtubules, which have been studied for over a quarter of a century. We also present some prospective on future endeavors to determine the molecular mechanisms that control microtubule rigidity. - The mechanochemistry of integrated motor protein complexes
Constantinou PE Diehl MR - J Biomech 43(1):31-37 (2010)
The assembly of molecular motor proteins into multi-unit protein complexes plays an important role in determining the intracellular transport and trafficking properties of many subcellular commodities. Yet, it is not known how proteins within these complexes interact and function collectively. Considering the established ties between motor transport and diseases, it has become increasingly important to investigate the functional properties of these essential transport 'motifs'. Doing so requires that the composite motile and force-generating properties of multi-unit motor assemblies are characterized. However, such analyses are typically confounded by a lack of understanding of the links between the structural and mechanical properties of many motor complexes. New experimental challenges also emerge when one examines motor cooperation. Distributions in the mechanical microstates available to motor ensembles must be examined in order to fully understand the transpor! t behavior of multi-motor complexes. Furthermore, mechanisms by which motors communicate must be explored to determine whether motor groups can move cargo together in a truly cooperative fashion. Resolving these issues requires the development of experimental methods that allow the dynamics of complex systems of transport proteins to be monitored with the same precision available to single-molecule biophysical assays. Herein, we discuss key fundamental principles governing the function of motor complexes and their relation to mechanisms that regulate intracellular cargo transport. We also outline new experimental strategies to resolve these essential features of intracellular transport. - The biomechanical integrin
Baker EL Zaman MH - J Biomech 43(1):38-44 (2010)
The integrin lies at the center of our efforts to understand mechanotransduction in the human body. Over the past two decades, a wealth of information has yielded important insights into integrin structure and functioning in biochemical pathways; however, relatively little emphasis has been placed on mechanics. In this article, we review the current knowledge base of integrin mechanobiology by examining the role of integrins in stabilizing tissue structure, the mechanisms of integrin force transfer, the process of cell migration, and the pathology of cancer. In order to successfully address the gaps in cancer and other disease research going forward, future efforts of integrin mechanobiology must focus on examining cells in 3D environments and integrating our current understanding into computational models that predict the behavior of integrins in non-equilibrium interactions. - Combining mechanical and optical approaches to dissect cellular mechanobiology
Sen S Kumar S - J Biomech 43(1):45-54 (2010)
Mechanical force modulates a wide array of cell physiological processes. Cells sense and respond to mechanical stimuli using a hierarchy of structural complexes spanning multiple length scales, including force-sensitive molecules and cytoskeletal networks. Understanding mechanotransduction, i.e., the process by which cells convert mechanical inputs into biochemical signals, has required the development of novel biophysical tools that allow for probing of cellular and subcellular components at requisite time, length, and force scales and technologies that track the spatio-temporal dynamics of relevant biomolecules. In this review, we begin by discussing the underlying principles and recent applications of atomic force microscopy, magnetic twisting cytometry, and traction force microscopy, three tools that have been widely used for measuring the mechanical properties of cells and for probing the molecular basis of cellular mechanotransduction. We then discuss how such to! ols can be combined with advanced fluorescence methods for imaging biochemical processes in living cells in the context of three specific problem spaces. We first focus on fluorescence resonance energy transfer, which has enabled imaging of intra- and inter-molecular interactions and enzymatic activity in real time based on conformational changes in sensor molecules. Next, we examine the use of fluorescence methods to probe force-dependent dynamics of focal adhesion proteins. Finally, we discuss the use of calcium ratiometric signaling to track fast mechanotransductive signaling dynamics. Together, these studies demonstrate how single-cell biomechanical tools can be effectively combined with molecular imaging technologies for elucidating mechanotransduction processes and identifying mechanosensitive proteins. - Intrinsic extracellular matrix properties regulate stem cell differentiation
Reilly GC Engler AJ - J Biomech 43(1):55-62 (2010)
One of the recent paradigm shifts in stem cell biology has been the discovery that stem cells can begin to differentiate into mature tissue cells when exposed to intrinsic properties of the extracellular matrix (ECM), such as matrix structure, elasticity, and composition. These parameters are known to modulate the forces a cell can exert upon its matrix. Mechano-sensitive pathways subsequently convert these biophysical cues into biochemical signals that commit the cell to a specific lineage. Just as with well-studied growth factors, ECM parameters are extremely dynamic and are spatially- and temporally-controlled during development, suggesting that they play a morphogenetic role in guiding differentiation and arrangement of cells. Our ability to dynamically regulate the stem cell niche as the body does is likely a critical requirement for developing differentiated cells from stem cells for therapeutic applications. Here, we present the emergence of stem cell mechanobio! logy and its future challenges with new biomimetic, three-dimensional scaffolds that are being used therapeutically to treat disease. - Emergent morphogenesis: Elastic mechanics of a self-deforming tissue
Davidson LA Joshi SD Kim HY von Dassow M Zhang L Zhou J - J Biomech 43(1):63-70 (2010)
Multicellular organisms are generated by coordinated cell movements during morphogenesis. Convergent extension is a key tissue movement that organizes mesoderm, ectoderm, and endoderm in vertebrate embryos. The goals of researchers studying convergent extension, and morphogenesis in general, include understanding the molecular pathways that control cell identity, establish fields of cell types, and regulate cell behaviors. Cell identity, the size and boundaries of tissues, and the behaviors exhibited by those cells shape the developing embryo; however, there is a fundamental gap between understanding the molecular pathways that control processes within single cells and understanding how cells work together to assemble multicellular structures. Theoretical and experimental biomechanics of embryonic tissues are increasingly being used to bridge that gap. The efforts to map molecular pathways and the mechanical processes underlying morphogenesis are crucial to understandi! ng: (1) the source of birth defects, (2) the formation of tumors and progression of cancer, and (3) basic principles of tissue engineering. In this paper, we first review the process of tissue convergent extension of the vertebrate axis and then review models used to study the self-organizing movements from a mechanical perspective. We conclude by presenting a relatively simple "wedge-model" that exhibits key emergent properties of convergent extension such as the coupling between tissue stiffness, cell intercalation forces, and tissue elongation forces. - Neural mechanobiology and neuronal vulnerability to traumatic loading
Laplaca MC Prado GR - J Biomech 43(1):71-78 (2010)
In order to understand the physical tolerance of neurons to traumatic insults, engineers and neuroscientists have attempted to reproduce the biomechanical environment during a traumatic event using in vitro injury systems with isolated components of the nervous system. This approach allows one to begin to unravel the underlying molecular and biochemical mechanisms that lead to cell dysfunction and death as a function of mechanical inputs. Excess mechanical force and deformation causes structural and functional breakdown, including several key deleterious cellular processes, such as membrane damage, an upset of calcium homeostasis, glutamate release, cell death, and caspase-mediated proteolysis. Understanding of the mechanotransduction events, however, that lead to cellular failure and dysfunction, are not well understood. Mechanically characterized cellular models of traumatic loading are critical to the improved understanding of mechanotransduction in the context of n! eural injury, the improvement of protective systems, and to provide a controlled setting for testing therapeutic interventions. In this review of the cellular mechanics of traumatic neural loading, we focus on the backdrop and motivation for studying mechanical thresholds in neurons and glial cells and discuss some of the acute responses that may help elucidate improved tolerance criteria and illuminate future research directions. - Exogenous and endogenous force regulation of endothelial cell behavior
Califano JP Reinhart-King CA - J Biomech 43(1):79-86 (2010)
Endothelial cells live in a dynamic environment where they are constantly exposed to external hemodynamic forces and generate cytoskeletal-based endogenous forces. These exogenous and endogenous forces are critical regulators of endothelial cell health and blood vessel maintenance at all generations of the vascular system, from large arteries to capillary beds. The first part of this review highlights the role of the primary exogenous hemodynamic forces of shear, cyclic strain, and pressure forces in mediating endothelial cell response. We then discuss the emergent role of the mechanical properties of the extracellular matrix and of cellular endogenous force generation on endothelial cell function, implicating substrate stiffness and cellular traction stresses as important mediators of endothelial cell health. The intersection of exogenous and endogenous forces on endothelial cell function is discussed, suggesting some of the many remaining questions in the field of en! dothelial mechanobiology. - Mechano-potential etiologies of aortic valve disease
David Merryman W - J Biomech 43(1):87-92 (2010)
Aortic valve leaflets experience varying applied loads during the cardiac cycle. These varying loads act on both cell types of the leaflets, endothelial and interstitial cells, and cause molecular signaling events that are required for repairing the leaflet tissue, which is continually damaged from the applied loads. However, with increasing age, this reparative mechanism appears to go awry as valve interstitial cells continue to remain in their 'remodeling' phenotype and subsequently cause the tissue to become stiff, which results in heart valve disease. The etiology of this disease remains elusive; however, multiple clues are beginning to coalesce and mechanical cues are turning out to be large predicators of cellular function in the aortic valve leaflets, when compared to the cells from the pulmonary valve leaflets, which are under a significantly less demanding mechanical loading regime. Finally, this paper discusses the mechanical environment of the constituti! ve cell populations, mechanobiological processes that are currently unclear, and a mechano-potential etiology of aortic disease will be presented. - Mechanobiology of cardiomyocyte development
Jacot JG Martin JC Hunt DL - J Biomech 43(1):93-98 (2010)
Cardiac cells are under constant, self-generated mechanical stress which can affect the differentiation of stem cells into cardiac myocytes, the development of differentiated cells and the maturation of cells in neonatal mammals. In this article, the effects of direct stretch, electrically induced beating and substrate elasticity on the behavior and development of cardiomyocytes are reviewed, with particular emphasis on the effects of substrate stiffness on cardiomyocyte maturation. In order to relate these observations to in vivo mechanical conditions, we isolated the left ventricle of Black Swiss mice from embryonic day 13.5 through post-natal day 14 and measured the elastic modulus of the epicardium using atomic force microscope indentation. We found that the elastic modulus of the epicardium significantly changes at birth, from an embryonic value of 12±4 kPa to a neonatal value of 39±7 kPa. This change is in the range shown to significantly affect the development! of neonatal cardiomyocytes. - Recent advances and new opportunities in lung mechanobiology
Tschumperlin DJ Boudreault F Liu F - J Biomech 43(1):99-107 (2010)
Lung function is inextricably linked to mechanics. On short timescales every breath generates dynamic cycles of cell and matrix stretch, along with convection of fluids in the airways and vasculature. Perturbations such airway smooth muscle shortening or surfactant dysfunction rapidly alter respiratory mechanics, with profound influence on lung function. On longer timescales, lung development, maturation, and remodeling all strongly depend on cues from the mechanical environment. Thus mechanics has long played a central role in our developing understanding of lung biology and respiratory physiology. This concise review focuses on progress over the past 5 years in elucidating the molecular origins of lung mechanical behavior, and the cellular signaling events triggered by mechanical perturbations that contribute to lung development, homeostasis, and injury. Special emphasis is placed on the tools and approaches opening new avenues for investigation of lung behavior at i! ntegrative cellular and molecular scales. We conclude with a brief summary of selected opportunities and challenges that lie ahead for the lung mechanobiology research community. - Boning up on Wolff's Law: Mechanical regulation of the cells that make and maintain bone
Chen JH Liu C You L Simmons CA - J Biomech 43(1):108-118 (2010)
Bone tissue forms and is remodeled in response to the mechanical forces that it experiences, a phenomenon described by Wolff's Law. Mechanically induced formation and adaptation of bone tissue is mediated by bone cells that sense and respond to local mechanical cues. In this review, the forces experienced by bone cells, the mechanotransduction pathways involved, and the responses elicited are considered. Particular attention is given to two cell types that have emerged as key players in bone mechanobiology: osteocytes, the putative primary mechanosensors in intact bone; and osteoprogenitors, the cells responsible for bone formation and recently implicated in ectopic calcification of cardiovascular tissues. Mechanoregulation of bone involves a complex interplay between these cells, their microenvironments, and other cell types. Thus, dissection of the role of mechanics in regulating bone cell fate and function, and translation of that knowledge to improved therapies, re! quires identification of relevant cues, multifactorial experimental approaches, and advanced model systems that mimic the mechanobiological environment. - Musculoskeletal mechanobiology: Interpretation by external force and engineered substratum
McCullen SD Haslauer CM Loboa EG - J Biomech 43(1):119-127 (2010)
Mechanobiology aims to discover how the mechanical environment affects the biological activity of cells and how cells' ability to sense these mechanical cues is converted into elicited cellular responses. Musculoskeletal mechanobiology is of particular interest given the high mechanical loads that musculoskeletal tissues experience on a daily basis. How do cells within these mechanically active tissues interpret external loads imposed on their extracellular environment, and, how are cell–substrate interactions converted into biochemical signals? This review outlines many of the main mechanotransduction mechanisms known to date, and describes recent literature examining effects of both external forces and cell–substrate interactions on musculoskeletal cells. Whether via application of external forces and/or cell–substrate interactions, our understanding and regulation of musculoskeletal mechanobiology can benefit by expanding upon traditional models, and sheddin! g new light through novel investigative approaches. Current and future work in this field is focused on identifying specific forces, stresses, and strains at the cellular and tissue level through both experimental and computational approaches, and analyzing the role of specific proteins through fluorescence-based investigations and knockdown models. - Mechanics and mechanobiology of mesenchymal stem cell-based engineered cartilage
Huang AH Farrell MJ Mauck RL - J Biomech 43(1):128-136 (2010)
In this review, we outline seminal and recent work highlighting the potential of mesenchymal stem cells (MSCs) in producing cartilage-like tissue equivalents. Specific focus is placed on the mechanical properties of engineered MSC-based cartilage and how these properties relate to that of engineered cartilage based on primary chondrocytes and to native tissue properties. We discuss current limitations and/or concerns that must be addressed for the clinical realization of MSC-based cartilage therapeutics, and provide some insight into potential underpinnings for the observed deviations from chondrocyte-based engineered constructs. We posit that these differences reveal specific deficits in terms of our description of chondrogenesis, and suggest that new benchmarks must be developed towards this end. Further, we describe the growing body of literature on the mechanobiology of MSC-based cartilage, highlighting positive findings with regards to the furtherance of the chond! rogenic phenotype. We likewise discuss the failure of early molecular changes to translate directly into engineered constructs with improved mechanical properties. Finally, we highlight recent work from our group and others that may point to new strategies for enhancing the formation of engineered cartilage based on MSCs. - Cellular mechanobiology of the intervertebral disc: New directions and approaches
Hsieh AH Twomey JD - J Biomech 43(1):137-145 (2010)
The more we learn about the intervertebral disc (IVD), the more we come to appreciate the intricacies involved in transmission of forces through the ECM to the cell, and in the biological determinants of its response to mechanical stress. This review highlights recent developments in our knowledge of IVD physiology and examines their impact on cellular mechanobiology. Discussion centers around the continually evolving cellular and microstructural anatomy of the nucleus pulposus (NP) and the annulus fibrosus (AF) in response to complex stresses generated in support of axial load and spinal motion. Particular attention has been given to cells from the immature NP and the interlamellar AF, and assessment of their potential mechanobiologic contributions to the health and function of the IVD. In addition, several innovative approaches that have been brought to bear on studying the interplay between disc cells and their micromechanical environment are discussed. Techniques f! or "engineering" cellular function and technologies for fabricating more structurally defined biomaterial scaffolds have recently been employed in disc research. Such tools can be used to elucidate the biological and physical mechanisms by which different IVD cell populations are regulated by mechanical stress, and contribute to advancement of preventative and therapeutic measures. - The myofibroblast: Paradigm for a mechanically active cell
Hinz B - J Biomech 43(1):146-155 (2010)
Tissues lose mechanical integrity when our body is injured. To rapidly restore mechanical stability a multitude of cell types can jump into action by acquiring a reparative phenotype—the myofibroblast. Here, I review the known biomechanics of myofibroblast differentiation and action and speculate on underlying mechanisms. Hallmarks of the myofibroblast are secretion of extracellular matrix, development of adhesion structures with the substrate, and formation of contractile bundles composed of actin and myosin. These cytoskeletal features not only enable the myofibroblast to remodel and contract the extracellular matrix but to adapt its activity to changes in the mechanical microenvironment. Rapid repair comes at the cost of tissue contracture due to the inability of the myofibroblast to regenerate tissue. If contracture and ECM remodeling become progressive and manifests as organ fibrosis, the outcome of myofibroblast activity will have more severe consequences than ! the initial damage. Whereas the pathological consequences of myofibroblast occurrence are of great interest for physicians, their mechano-responsive features render them attractive for physicists and bioengineers. Their well developed cytoskeleton and responsiveness to a plethora of cytokines fascinate cell biologists and biochemists. Finally, the question of the myofibroblast origin intrigues stem cell biologists and developmental biologists—what else can you ask from a truly interdisciplinary cell? - Shape, loading, and motion in the bioengineering design, fabrication, and testing of personalized synovial joints
Williams GM Chan EF Temple-Wong MM Bae WC Masuda K Bugbee WD Sah RL - J Biomech 43(1):156-165 (2010)
With continued development and improvement of tissue engineering therapies for small articular lesions, increased attention is being focused on the challenge of engineering partial or whole synovial joints. Joint-scale constructs could have applications in the treatment of large areas of articular damage or in biological arthroplasty of severely degenerate joints. This review considers the roles of shape, loading and motion in synovial joint mechanobiology and their incorporation into the design, fabrication, and testing of engineered partial or whole joints. Incidence of degeneration, degree of impairment, and efficacy of current treatments are critical factors in choosing a target for joint bioengineering. The form and function of native joints may guide the design of engineered joint-scale constructs with respect to size, shape, and maturity. Fabrication challenges for joint-scale engineering include controlling chemo-mechano-biological microenvironments to promote ! the development and growth of multiple tissues with integrated interfaces or lubricated surfaces into anatomical shapes, and developing joint-scale bioreactors which nurture and stimulate the tissue with loading and motion. Finally, evaluation of load-bearing and tribological properties can range from tissue to joint scale and can focus on biological structure at present or after adaptation. - Modeling collagen remodeling
Baaijens F Bouten C Driessen N - J Biomech 43(1):166-175 (2010)
Collagen is the main load bearing protein in many soft tissues, and in cardiovascular tissues in particular. In many tissues collagen has a specific architecture that is crucial for the biomechanical function of the tissue. Typical examples are the hammock-shaped collagen architecture in heart valves and a helical pattern in arteries. One of the objectives in cardiovascular tissue engineering is the reconstitution of this architecture. It is hypothesized that the architecture is mediated by mechanical stimulation. Computational models were developed to predict the mechanoregulation of the collagen architecture. This review recapitulates the key modeling assumptions and results achieved to date.
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